1. Field of the Invention
The present invention relates to methods of alleviating restenosis post-percutaneous transluminal coronary angioplasty (PTCA) or other coronary arterial intervention, and more particularly, to the use of ancrod to prevent restenosis in the coronary arteries.
2. Background of the Prior Art
Restenosis following PTCA is a significant limitation to the application of this otherwise useful revascularization technique. Restenosis occurs with varying frequency, and is generally accepted to be 25%-45%, depending on a number of factors including the site of the lesion, residual gradient post PTCA, sex (male), smoking and/or diabetes, skill of operator, method and timing of followup, and balloon size.
The problem typically manifests within 12 weeks to six months post procedure, and presents as recurrent angina in many cases, although "silent" restenosis occurs as well where ischemia recurs without overt clinical manifestation. This problem will become increasingly severe, as estimates that 400,000 or more procedures will be performed annually by the year 1993.
Clinical trials with other interventional methods such as atherectomy and intracoronary laser ablation suffer from the same restenosis problem, probably with similar frequencies of occurrence. Attempts to prevent restenosis with systemic drug therapy such as anti-platelet agents, anticoagulants, corticosteroids, and calcium channel blockers have uniformly failed to reduce its occurrence.
The histologic appearance of the recurrent lesion in restenosis is distinctly different from the atheromatous process of the original lesion. The atherosclerotic process evolves over many decades, beginning as flat, fatty streaks consisting of lipid-laden smooth muscle cells. Over time, these lesions evolve in complexity, becoming grossly fibrous plaques with ulceration, calcification, thrombosis and/or hemorrhage into the vessel wall. Microscopically, the atherosclerotic lesion has histological features of disruption and replication of the internal elastic lamina, spindle and smooth cell proliferation, interstitial fibrosis, intracellular and interstitial lipid accumulation, fibrin deposition, calcification, hemorrhage, thrombosis, capillary proliferation and macrophage infiltration. This process may be a response to injury. Most atherosclerotic lesions are endothelialized continuously with adjacent vascular endothelium.
The histopathology of restenosis after PTCA has been recently elucidated with the advent of percutaneous atherectomy procedures whereby such lesions are removed intact. In contrast to the atheromatous lesion, restenotic segments consist of a proliferation of cells and interstitial material resembling normal connective tissue with smooth muscle involvement. The lesion of restenosis thus differs distinctly from the original atherosclerotic disease both in time course of development and histologic appearance. It is likely that restenosis represents a zealous natural healing process of damaged coronary arterial walls with neointimal tissue impinging significantly on the vessel lumen.
If an agent or process could be found whereby restenosis could be significantly reduced or eliminated, a major advance in clinical care would be achieved. Savings of much morbidity, time, emotional investment, and economic cost could be realized by patients with coronary artery disease undergoing PTCA or other percutaneous coronary revascularization, in addition to improving patient safety.